What two factors must be considered when establishing the dosage of an antimicrobial drug

Note: This is a brief description of some important concepts in the use of susceptibility data to guide therapy. This information is in no way intended to supersede clinical judgment, information provided in package inserts or textbooks, nor to replace a thorough review of the many fine books and information sources on antimicrobial use. For further information and eloquent descriptions of this topic, it is suggested that you consult the following source: Small Animal Clinical Pharmacology and Therapeutics by Dawne Merton Boothe published by W.B. Saunders Co in 2001.

The efficacy of a particular antimicrobial drug in treating an infection depends on a variety of factors including those associated with the host, the drug, and the bacterium. The two factors that we will consider here are those associated with the drug and the "bug." Each antimicrobial drug has characteristics that should be considered as part of the drug selection process. These include: toxicity, mode of action (bacteriostatic vs. bacteriocidal), tissue distribution, plasma half-life, achievable plasma concentrations, spectrum, and cost among others. Much of this information is available on the package insert for the drug or a PDR.

The bacteria involved in the infectious process have individual characteristics of sensitivity/resistance to certain drugs, rapidity with which the bacteria acquire resistance to various classes of drugs, and site of persistence and growth (e.g. intracellular vs extracellular). The MSU VDL provides information regarding the susceptibility/resistance of individual bacterial isolates to various drugs and drug classes by providing either quantitative (MIC) and/or qualitative (S, I, R) antimicrobial susceptibility results.

The MIC is particularly valuable because this value can be used to compare the relative efficacy of different drugs and to calculate doses that may need to be customized in particularly challenging infections. Simply defined, the MIC is the minimum concentration of the drug that will inhibit the in vitro growth of the organism and is specific to the organism isolated and the drug. This means that the drug concentration at the site of infection should be at least equal to the MIC value. Package inserts and PDR's and various textbooks (citations below) contain information about achievable drug concentrations in various tissues with various dosing regimens. For some drugs these values have been established in various animal species but in many cases, the data must be extrapolated from human testing.

Another important variable in using MIC data is the so called "Resistant Breakpoint MIC" and this is the approximate drug concentration that can be reasonably achieved safely in the plasma using the normal dose and route of administration of the drug. Thus the Breakpoint MIC takes into account the clinical pharmacology of the drug and is specific for the host, dose, and drug but is not usually organism specific. Resistant Breakpoint MICs are determined by testing organizations. The VDL uses (when available) the breakpoints set by the Clinical Laboratory Standards Institute (CLSI). These breakpoints are available free of charge at https://clsi.org/standards/products/free-resources/access-our-free-resources.

Armed with the organism MIC measured at the the Resistant Breakpoint MIC, you can begin to compare the relative efficacy of various antimicrobials to treat a given infection. We are frequently asked if the way to use MIC data to choose a drug is to use the drug with the "lowest number." The answer is an unequivocal NO! The MICs for various drugs must be compared as they relate to the Resistance Breakpoint MIC for that drug. The Resistant Breakpoint MIC is divided by the measured MIC provided by the MSU VDL to derive an efficacy ratio—or a measure of how far the measured MIC is from the Resistant Breakpoint for that drug. A drug with a high efficacy ratio should be more effective that a drug with a lower efficacy ratio would be.

Confused yet? An example might be helpful. Suppose the measured MIC for an E. coli isolate from a dog was 1 ug/ml for enrofloxacin and 1 ug/ml for gentamicin. Using the chart provided, the Resistant Breakpoint MIC's for these drugs are determined to be >4 ug/ml for enrofloxacin (at the 5mg/kg dose) and >8 ug/ml for gentamicin. Therefore, the efficacy ratio for enrofloxacin in this particular infection would be 4 (4 divided by 1) and that for gentamicin would be 8 (8 divided by 1). The drug with the higher efficacy ratio, in this case gentamicin, would be predicted to be more effective in this infection. This type of calculation can be repeated to compare a whole series of drugs and this information can be factored in with the many other considerations in choosing an antimicrobial.

Another example: Here is an example (shaded green) of a typical report issued by the MSU VDL on a skin culture from a dog:

Moderate numbers of Staphylococcus pseudintermedius

In this case, the data from the MSU VDL is shaded in light green and the analysis by the veterinarian in light blue. Assume you want to use a drug that is good for skin infections and is available for PO use which narrows your choices somewhat. Next, to compare the relative efficacy of the drug choices, you look up the Resistant Breakpoint MIC and calculate the Efficacy ratio as described above. In this example, there are several reasonable choices but it appears that both clindamycin and erythromycin would be a great choice as it has the highest efficacy ratio.

References and other sources of information:

Small Animal Clinical Pharmacology and Therapeutics by Dawne Merton Boothe, W.B. Saunders Co., 2001.

Antimicrobial Therapy in Veterinary Medicine, Third Edition, J.F. Prescott, J.D. Baggot, and R.D. Walker, Eds., Iowa State University Press, 2000.

CLSI. Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for Bacteria Isolated From Animals. 5th ed. CLSI standard VET01. Wayne, PA: Clinical and Laboratory Standards Institute; 2018.

CLSI. Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for Bacteria Isolated From Animals. 4th ed. CLSI supplement VET08. Wayne, PA: Clinical and Laboratory Standards Institute; 2018.

CLSI. Performance Standards for Antimicrobial Susceptibility Testing. 28th ed. CLSI supplement M100. Wayne, PA: Clinical and Laboratory Standards Institute; 2018.

Physicians Drug Reference

Package inserts from antimicrobials